Disruption of male fertility-critical Dcaf17 dysregulates mouse testis transcriptome

Area of Science:

• Reproductive Biology
• Molecular Genetics
• Proteostasis

Background:

• The ubiquitin proteasome system is vital for maintaining protein homeostasis (proteostasis) and spermatogenic functions during mammalian spermatogenesis.
• DCAF17, a substrate receptor in the CRL4 E3 Ligase complex, is essential for male fertility; its absence leads to oligoasthenoteratozoospermia and infertility in mice.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying male infertility caused by DCAF17 disruption.
• To analyze the impact of DCAF17 deficiency on gene expression profiles in mouse testes.

Main Methods:

• RNA-sequencing (RNA-seq) based gene expression profiling was performed on testes from 3-week and 8-week old wild-type and Dcaf17-disrupted mutant mice.
• Differential gene expression analysis identified up- and down-regulated genes (DEGs) at both time points.
• Gene Ontology (GO) analysis was used to identify affected biological processes.

Main Results:

• DCAF17 disruption significantly altered gene expression in mouse testes, with a higher proportion of down-regulated genes observed at 8 weeks (68%) compared to 3 weeks (56%).
• Affected biological processes included proteolysis, transcriptional regulation, and chromatin remodeling.
• DCAF17 disruption led to the upregulation of somatic genes and downregulation of germline-associated genes, with a notable percentage of DEGs implicated in male reproductive phenotypes.

Conclusions:

• DCAF17 disruption directly or indirectly impairs testicular proteostasis and alters the testicular transcriptional signature.
• The observed changes in gene expression, particularly the differential regulation of spermatogonial, spermatocyte, and round spermatid-expressed genes, contribute to the observed male infertility phenotype.